Abuse-resistant drug formulations
Disclosed are abuse resistant oral pharmaceutical compositions that reduce the likelihood of improper administration of drugs that are susceptible to abuse. The oral pharmaceutical formulations contain abuse deterrent agents that cause discomfort to the user when administered in an improper manner and make the extraction of an active ingredient more difficult. Methods of making and using the compositions are also disclosed.
1. An abuse-resistant liquid pharmaceutical composition comprising an immediate release unit dose of a mixture of an effective amount of at least one pharmaceutically active agent susceptible to abuse, an organic vehicle, a surfactant, a co-solvent, and a viscosity-building polymer;
wherein the organic vehicle, surfactant, and co-solvent co-elute with the pharmaceutically active agent when exposed to a solvent;
wherein the organic vehicle is a C6-C18 fatty acid, a C6-C18 fatty acid mono-, di- or tri-glyceride, a C6-C18 fatty acid propylene glycol mono- or di-ester, a C6-C18 fatty acid polyethylene glycol ester, a vegetable oil, or a mixture of two or more thereof, and is present in an amount of about 50% to about 90% by weight, based on the total weight of the composition;
wherein the surfactant is dioctyl sodium sulfosuccinate, sodium lauryl sulfate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-35 castor oil, PEG-8 glyceryl caprylate/caprate, PEG-6 glyceryl caprylate/caprate, PEG-40 hydrogenated castor oil, Macrogol 15 hydroxystearate, an ethylene oxide/propylene oxide block copolymer, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, tocopherol PEG succinate, polyoxyl 40 stearate, or a mixture of two or more thereof, and is present in an amount of about 2% to about 40% by weight, based on the total weight of the composition;
wherein the viscosity-building polymer is PEG-2M, PEG-5M, PEG-7M, PEG-14M, PEG-23M, PEG-45M, PEG-90M, or a combination of two or more thereof, and is present in an amount of about 0.5% to about 20% by weight, based on the total weight of the composition, so that it does not slow an immediate release of the pharmaceutically active agent from a single unit-dose administration, but slows the immediate release of the pharmaceutically active agent from a multiple unit-dose administration.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutically active agent susceptible to abuse is an opioid, a barbiturate or an amphetamine.
3. The pharmaceutical composition of claim 1 , wherein the pharmaceutically active agent susceptible to abuse is selected from the group consisting of codeine, phenazocine, tilidine, tramadol, meperidine, sufentanil, prodine, methadone, pentazocine, oxycodone, oxymorphone, hydrocodone, hydromorphone, tapentadol, morphine, buprenorphine, and fentanyl, or a pharmaceutically acceptable salt, ester or solvate thereof.
4. The pharmaceutical composition of claim 1 , wherein the pharmaceutically active agent susceptible to abuse is selected from the group consisting of alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamines, amphetaminil, amobarbital, anileridine, apocodeine, barbital, benzylmorphine, bezitramide, bromazepam, brotizolam, butobarbital, butorphanol, camazepam, chlorodiazepoxide, clobazam, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphen, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, fencamfamine, fenethylline, fenproporex, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydroxypethidine, hydroxymethyl morphinane, isomethadone, ketazolam, ketobemidone, levomethadyl acetate, levomethadone, levorphanol, levophenacylmorphane, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meprobamate, meptazinol, metazocine, methylmorphine, methamphetamine, methaqualone, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, myrophine, nabilone, nalbuphine, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, nor levorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, pemoline, pentobarbital, pethidine, phenadoxone, phenomorphan, phenoperidine, piminodine, pholcodine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, temazepam, tetrazepam, triazolam, vinylbital, and zolpidem, or a pharmacologically acceptable salt, ester or solvate thereof.
5. The pharmaceutical composition of claim 1 , further comprising an effective amount of an analgesic.
6. The pharmaceutical composition of claim 5 , wherein the analgesic is acetaminophen.
7. The pharmaceutical composition of claim 1 , wherein the organic vehicle is selected from the group consisting of caprylic acid, capric acid, oleic acid, palmitic acid, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl caprylate, caprate, propylene glycol monocaprate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dilaurate, polyethylene glycol (PEG)-4 glyceryl caprylate, caprate, PEG-6 glyeryl linoleate, PGE-6 glyceryl linoleate, PEG-6 glyceryl oleate, caprylic/capric triglyceride, propylene glycol dicaprylate/dicaprate, soyabean oil and mixtures of two or more thereof.
8. The pharmaceutical composition of claim 1 , wherein the co-solvent is a liquid ester.
9. The pharmaceutical composition of claim 8 , wherein the co-solvent is selected from the group consisting of triethyl citrate, propylene glycol, a polyethylene glycol, triacetin, diethylene glycol monoethyl ether, and mixtures of two or more thereof.
10. The pharmaceutical composition of claim 1 , wherein the co-solvent is present in an amount of about 10% to about 50%, by weight, based on the total weight of the composition.
11. The pharmaceutical composition of claim 1 , wherein the organic vehicle is glyceryl caprylate/caprate, soyabean oil, olive oil, oleic acid, Caprylic/Capric Triglyceride, fish oil, propylene glycol monocaprylate, or a combination of two or more thereof.
12. The pharmaceutical composition of claim 11 , wherein the co-solvent is propylene glycol, triethyl citrate, PEG-400 or a combination of two or more thereof.
13. The pharmaceutical composition of claim 1 , further comprises a buffering agent.
14. The pharmaceutical composition of claim 1 , further comprising an antioxidant.
15. The pharmaceutical composition of claim 14 , wherein the antioxidant is selected from the group consisting of alpha-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and combinations of two or more thereof.
16. The pharmaceutical composition of claim 1 , further comprising a viscosity-building agent selected from the group consisting of colloidal silicon dioxide, fumed silica, mesoporous silica and combinations of two or more thereof.
17. The pharmaceutical composition of claim 1 , further comprising an opioid receptor antagonist selected from the group consisting of naloxone, naltrexone and methyl naltrexone.
18. The pharmaceutical composition of claim 1 , wherein the pharmaceutically active agent is pre-treated with silica.
19. A method of rendering abuse resistant a pharmaceutically active agent susceptible to abuse, comprising preparing an immediate-release liquid pharmaceutical composition by mixing an effective amount of the pharmaceutically active agent, an organic vehicle, a surfactant, a co-solvent, and a viscosity-building polymer;
wherein the organic vehicle, surfactant, and co-solvent co-elute with the pharmaceutically active agent when exposed to a solvent,
wherein the organic vehicle is a C6-C18 fatty acid, a C6-C18 fatty acid mono-, di- or tri-glyceride, a C6-C18 fatty acid propylene glycol mono- or di-ester, a C6-C18 fatty acid polyethylene glycol ester, a vegetable oil, or a mixture of two or more thereof, and is present in an amount of about 50% to about 90% by weight, based on the total weight of the composition;
wherein the surfactant is dioctyl sodium sulfosuccinate, sodium lauryl sulfate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-35 castor oil, PEG-8 glyceryl caprylate/caprate, PEG-6 glyceryl caprylate/caprate, PEG-40 hydrogenated castor oil, Macrogol 15 hydroxystearate, an ethylene oxide/propylene oxide block copolymer, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, tocopherol PEG succinate, polyoxyl 40 stearate, or a mixture of two or more thereof, and is present in an amount of about 2% to about 40%, by weight, based on the total weight of the composition;
wherein the viscosity-building polymer is PEG-2M, PEG-5M, PEG-7M, PEG-14M, PEG-23M, PEG-45M, PEG-90M, or a combination of two or more thereof, and is present in an amount of about 0.5% to about 20% by weight, based on the total weight of the composition, so that it does not slow an immediate release of the pharmaceutically active agent from a single unit-dose administration, but slows the immediate release of the pharmaceutically active agent from a multiple unit-dose administration.
20. A method of deterring abuse of a pharmaceutically active agent susceptible to abuse, comprising administering the pharmaceutically active agent to a subject in need thereof, wherein the pharmaceutically active agent is formulated in a liquid pharmaceutical composition that comprises a mixture of an immediate release unit of a mixture of an effective amount of the pharmaceutically active agent, an organic vehicle, a surfactant, a co-solvent, and a viscosity-building polymer;
wherein the organic vehicle, surfactant, and co-solvent co-elute with the pharmaceutically active agent when exposed to a solvent,
wherein the organic vehicle is a C6-C18 fatty acid, a C6-C18 fatty acid mono-, di- or tri-glyceride, a C6-C18 fatty acid propylene glycol mono- or di-ester, a C6-C18 fatty acid polyethylene glycol ester, a vegetable oil, or a mixture of two or more thereof, and is present in an amount of about 50% to about 90% by weight, based on the total weight of the composition;
wherein the surfactant is dioctyl sodium sulfosuccinate, sodium lauryl sulfate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-35 castor oil, PEG-8 glyceryl caprylate/caprate, PEG-6 glyceryl caprylate/caprate, PEG-40 hydrogenated castor oil, Macrogol 15 hydroxystearate, an ethylene oxide/propylene oxide block copolymer, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, tocopherol PEG succinate, polyoxyl 40 stearate, or a mixture of two or more thereof, and is present in an amount of about 2% to about 40%, by weight, based on the total weight of the composition;
wherein the viscosity-building polymer is PEG-2M, PEG-5M, PEG-7M, PEG-14M, PEG-23M, PEG-45M, PEG-90M, or a combination of two or more thereof, and is present in an amount of about 0.5% to about 20% by weight, based on the total weight of the composition, so that it does not slow an immediate release of the pharmaceutically active agent from a single unit-dose administration, but slows the immediate release of the pharmaceutically active agent from a multiple unit-dose administration.